Interactive Database Research Articles

Stanniocalcin 2 Regulates Autophagy and Ferroptosis in Mammary Epithelial Cells of Dairy Cows Through the Mechanistic Target of Rapamycin Complex 1 Pathway

BackgroundStanniocalcin 2 (STC2), a glycoprotein hormone, is extensively expressed in various organs and tissues, particularly in the mammary gland. STC2 plays a crucial role in enabling cells to adapt to stress conditions and avert apoptosis. The efficiency of milk production is closely linked to both the quantity and quality of mammary cells. Yet, there remains a dearth of research on the impact of STC2 on mammary cells’ activity in dairy cows. ObjectivesThe objective of this study was to investigate the effects of STC2 on the viability of mammary epithelial cells in dairy cows and to elucidate the underlying mechanisms. MethodsFirst, the Gene Expression Profiling and Interactive Analysis database was employed to perform survival analysis on STC2 expression in relation to prognosis using The Cancer Genome Atlas and GETx data. Subsequently, the basic physical and chemical properties, gene expression, and potential signaling pathways involved in the growth of dairy cow mammary epithelial cells were determined using STC2 knockdown. ResultsSTC2 knockdown significantly suppressed autophagy in mammary epithelial cells of dairy cows. Moreover, STC2 knockdown upregulated glutathione peroxidase 4 protein expression, elicited an elevation in lipid ROS concentrations, and inhibited the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, consequently repressing downstream genes involved in lipid synthesis regulated by mTORC1 and ultimately inducing ferroptosis. ConclusionsThe findings of our study suggest that STC2 suppresses autophagy and ferroptosis through the activation of mTORC1. Mechanically, STC2 exerts an inhibitory effect on ferroptosis by activating antioxidative stress-related proteins, such as glutathione peroxidase 4, to suppress lipid ROS production and stimulating the mTORC1 signaling pathway to enhance the expression of genes associated with lipid synthesis.

Is Program Director Gender Associated With Gender Diversity Among Orthopaedic Surgery Residency Programs?

Women remain underrepresented in leadership roles, faculty roles, and among residents in orthopaedic surgery. It has been suggested that having women in leadership positions in orthopaedic surgery may help to increase the gender diversity of residency programs. However, to our knowledge, no study has explored the relationship, if any, between the gender of the residency program director and the percentage of women in the residency program. (1) Is the program director's gender associated with differences in the percentage of women orthopaedic surgery residents? (2) Do women and men differ in the time to appointment of program director? A list of 207 orthopaedic surgery residencies was obtained from the Accreditation Council for Graduate Medical Education (ACGME) website for the academic year 2021 to 2022. The study excluded 6% (13) of programs; 4% (8) were those without ACGME accreditation and those with initial accreditation, and 2% (5) did not have updated 2021 to 2022 resident lists. Descriptive information on 194 programs was obtained from publicly accessible resources from July 2021 through July 2022. The institution's website and the American Medical Association's (AMA) Fellowship and Residency Electronic Interactive Database (FREIDA) was used to collect residency program characteristics and resident demographics [ 2 ]. Doximity, Healthgrades, and LinkedIn were used to further collect current orthopaedic surgery residency program director demographics, including gender, age, and education/training history. To determine gender, photographs and pronouns (she/her/hers or he/him/hers) used in their biographies were used first. To confirm this, secondary sources were used including their NPI profile, which lists gender; Doximity; and their LinkedIn profile. Scopus was used to analyze research output by the program directors-using the Hirsch index (h-index) as the primary bibliometric metric. A total of 194 program directors were identified, of whom of 12% (23) were women and 88% (171) were men. Of the 4421 total residents among these programs, 20% (887) were women and 80% (3534) were men. A univariate analysis comparing program directors was conducted, with continuous variables analyzed using an independent-sample t-test and categorical variables analyzed using a Pearson chi-square test. With the numbers available, a post hoc statistical power calculation indicated that we could detect an 32% difference in the percentage of women in a program as significant with 80% power at the p < 0.05 level, whereas we might have been underpowered to discern smaller differences than that. With the numbers available, we found no difference in the percentage of women in residency programs run by women program directors than in programs in which the program director was a man (22% [125 of 558] versus 20% [762 of 3863], mean difference 2% [95% CI -1.24% to 7.58%]; p = 0.08). Comparing women to men program directors, women had fewer years between residency completion and appointment to the position of program director (8 ± 2 years versus 12 ± 7 years, mean difference 4 years [95% CI 2.01 to 7.93 years]; p = 0.02) and had a lower mean h-index (7 ± 4 versus 11 ± 11, mean difference 4 [95% CI 1.70 to 6.56]; p = 0.03) and number of publications (24 ± 23 versus 41 ± 62, mean difference 17 [95% CI 3.98 to 31.05]; p = 0.01), although they did not differ in terms of their advanced degrees, duration of training, or likelihood of having taken a fellowship. Orthopaedic residency programs that were run by women did not contain a higher percentage of women residents, suggesting that the gender of the individual in that role may not be as important as has been speculated by others. Future studies should investigate the intersectionality of gender, race, and ethnicity of residents, program directors, and current faculty. The fact that women were placed in program director roles earlier in career may also carry special jeopardy for them. Those roles are difficult and can impair a faculty member's ability to conduct individual research, which often is key to further academic promotions. Given that and the fact that the gender of the program director was not associated with differences in gender composition of residency programs, we believe that increasing mentorship and access to pipeline programs will help promote diversity in residency programs.

Residency Program Website Content May Not Meet Applicant Needs

Background: Residency program applicants use a variety of resources during the application cycle. Program websites can vary substantially, and it is unclear how the website information is used by applicants. We aimed to determine the most popular information source used by applicants. We also sought to identify specific online content that was deemed important in the decision-making process. Methods: A survey was distributed to fourth-year medical students at an academic institution. Demographic information was collected, and the importance of various online resources was gauged using a Likert scale. Subgroup analysis was performed for procedural versus non-procedural specialty applicants. Results: 91 of the 169 fourth-year medical students (54%) completed the survey. The most utilized sources for the students were residency program websites (41%), the Fellowship and Residency Electronic Interactive Database (FREIDA) website (36%), and the Doximity website (14%). The most valued (Likert scale of 4 and 5) website content for the students included information on resident wellness (86%), resident fellowship acquisition (85%), faculty data (84%), residency location and resident lifestyle (81%), and application point of contact (79%). There were significant differences between what procedural specialty applicants deemed important versus what those applying to non-procedural specialties deemed important. Conclusion: Residency program websites are commonly used among applicants during the residency match process. Content on resident wellness was highly valued irrespective of specialty choice; however, this information was often not present on residency websites. These findings may help guide website content development initiatives for residency programs to reflect applicant needs more adequately.

Early dementia detection with speech analysis and machine learning techniques

This in-depth study journey explores the context of natural language processing and text analysis in dementia detection, revealing their importance in a variety of fields. Beginning with an examination of the widespread and influence of text data. The dataset utilised in this study is from TalkBank's DementiaBank, which is basically a vast database of multimedia interactions built with the goal of examining communication patterns in the context of dementia. The various communication styles dementia patients exhibit when communicating with others are seen from a unique perspective by this specific dataset. Thorough data preprocessing procedures, including cleansing, tokenization, and structuring, are undertaken, with a focus on improving prediction capabilities through the combination of textual and non-textual information in the field of feature engineering. In the subsequent phase, the precision, recall, and F1-score metrics of Support Vector Machines (SVM), K-Nearest Neighbours (KNN), Random Forest, and Artificial Neural Networks (ANN) are assessed. Empirical facts are synthesized using text analysis methods and models to formulate a coherent conclusion. The significance of text data analysis, the revolutionary potential of natural language processing, and the direction for future research are highlighted in this synthesis. Throughout this paper, readers are encouraged to leverage text data to embark on their own adventures in the evolving, data-centric world of dementia detection.

Holistic Review of Applicants by the United States Postgraduate Training Programs Is Not Associated With the Percentage of Female Residents.

Introduction Given the underrepresentation of female physicians in most specialties and the aim of holistic review in residency applicationsto improve the diversity of matriculating resident physicians in the United States (US) postgraduate medical training programs, we examined the association between holistic review and female resident representation among US postgraduate training programs. Methods We conducted a cross-sectional survey of US postgraduate training programs to inquire about their use of holistic review for resident applications (independent variable). The primary outcome was the percentage of female residents in each program, which was obtained along with other program-level characteristics from the Fellowship and Residency Electronic Interactive Database Access (FREIDA) catalog in April 2023. We limited the analysis to the 10 specialties with the most training spots in 2022, including anesthesiology, emergency medicine, family medicine, internal medicine, neurology, obstetrics and gynecology, orthopedic surgery, pediatrics, psychiatry, and surgery (general). We also examined the interactions between holistic review and specialtyand the percentage of female facultyusing model comparison and simple slopes analyses. Results Of the 3,364 total programs surveyed from the 10 specialties, 222 (6.6%)responded. Responders and nonresponders had similar program-level characteristics, including program type (e.g., university, community), specialty, and reported minimum board examination scores. Of the 222 responders, 179 (80.6%) reported performingholistic review. The percentage of female residents was 49.0% (interquartile range 37.5 to 66.7) in the no holistic review group and 47.8% (35.4 to 65.0) in the holistic review group (median difference 0.9%, 95% confidence interval -6.7 to 8.3). Furthermore, there was no evidence of interaction between holistic review and either the specialty or the percentage of female faculty on the outcome of the percentage of female residents. Conclusions Holistic review of residency applications in this limited sample of US postgraduate training programs was not associated with the percentage of female residents. The role of holistic review in addressing the imbalance of male and female physicians in the healthcare workforce, particularly between specialties, remains unknown.

Data-driven modeling of core gene regulatory network underlying leukemogenesis in IDH mutant AML

Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of poorly differentiated myeloid cells, with a heterogenous mutational landscape. Mutations in IDH1 and IDH2 are found in 20% of the AML cases. Although much effort has been made to identify genes associated with leukemogenesis, the regulatory mechanism of AML state transition is still not fully understood. To alleviate this issue, here we develop a new computational approach that integrates genomic data from diverse sources, including gene expression and ATAC-seq datasets, curated gene regulatory interaction databases, and mathematical modeling to establish models of context-specific core gene regulatory networks (GRNs) for a mechanistic understanding of tumorigenesis of AML with IDH mutations. The approach adopts a new optimization procedure to identify the top network according to its accuracy in capturing gene expression states and its flexibility to allow sufficient control of state transitions. From GRN modeling, we identify key regulators associated with the function of IDH mutations, such as DNA methyltransferase DNMT1, and network destabilizers, such as E2F1. The constructed core regulatory network and outcomes of in-silico network perturbations are supported by survival data from AML patients. We expect that the combined bioinformatics and systems-biology modeling approach will be generally applicable to elucidate the gene regulation of disease progression.

Cyclin B1: A potential prognostic and immunological biomarker in pan-cancer.

Cyclin B1 (CCNB1) encodes a regulatory protein essential for the regulation of cell mitosis, particularly in controlling the G2/M transition phase of the cell cycle. Current research has implicated CCNB1 in the progression of various types of cancer, including gastric cancer, breast cancer, and non-small cell lung cancer. In this study, we conducted a pan-cancer analysis of CCNB1 to investigate its prognostic significance and immunological aspects. Our comprehensive investigation covered a wide range of analyses, including gene expression, promoter methylation, genetic alterations, immune infiltration, immune regulators, and enrichment studies. We utilized multiple databases and tools for this purpose, such as The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, the Human Protein Atlas (HPA), the University of Alabama at Birmingham CANcer data analysis Portal (UALCAN), the Gene Expression Profiling Interactive Analysis (GEPIA), the DNA Methylation Interactive Visualization Database (DNMIVD), the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Sangerbox, and cBioPortal. Data analyses were executed using GraphPad Prism software, R software, and various online tools. Our findings demonstrated a significant increase in CCNB1 expression across 28 cancer types. Elevated CCNB1 expression correlated with decreased overall survival (OS) in 11 cancer types and disease-free survival (DFS) in 12 cancer types. Additionally, DNA promoter methylation levels were significantly decreased in 14 cancer types. Furthermore, the study verified a significant association between CCNB1 expression and immune infiltration, immune modulators, microsatellite instability (MSI), and tumor mutational burden (TMB). Enrichment analysis indicated that CCNB1 is involved in multiple cellular pathways. Collectively, our results suggested that CCNB1 has the potential to serve as a valuable prognostic biomarker and may be a promising target for immunotherapy in various cancer types.

Functional Investigation and Two-sample Mendelian Randomization Study of Inguinal Hernia Hub Genes Obtained by Bioinformatics Analysis.

Inguinal hernia in adults is a common and frequent disease in surgery, prone to occur in the elderly or in those with a weak abdominal wall. Despite its prevalence, Molecular mechanisms underlying inguinal hernia formation are unclear. This study aims to identify potential gene markers for inguinal hernia and available drugs. Pubmed2Ensembl text mining was used to identify genes related to "inguinal hernia" keywords. The GeneCodis system was used to specify GO biological process terms and KEGG pathways defined in the Kyoto Encyclopedia of Genes and Genomes (KEGG). The STRING tool was used to construct protein-protein interaction networks, which were then visualized using Cytoscape.CytoHubba and Molecular Complex Detection were utilized to analyze the module (MCODE). A GO and KEGG analysis of gene modules was conducted using the DAVID platform database. Hub genes are those that are concentrated in prominent modules. The druggene interaction database was also used to identify potential drugs for inguinal hernia patients based on their interactions between the hub genes. Finally, a Mendelian randomization study was conducted based on genome-wide association studies to determine whether hub genes cause inguinal hernias. The identification of 96 genes associated with inguinal hernia was carried out using text mining techniques. It was constructed using PPI networks with 80 nodes and 476 edges, and the sequence of the genes was performed using CytoHubba. MCODE analysis identified three gene modules. Three modules contain 37 genes clustered as hub candidate genes associated with inguinal hernia patients. The PI3K-Akt, MAPK, AGE-RAGE, and HIF-1 pathways were found to be enriched in signaling pathways. Sixteen of the 37 genes were found to be targetable by 30 existing drugs. The relationship between hub genes and inguinal hernia was examined using Mendelian randomization. The research revealed nine genes that may be connected with inguinal hernia, such as POMC, CD40LG, TFRC, VWF, LOX, IGF2, BRCA1, TNF, and HGF in the plasma. By inverse variance weighting, ALB was associated with an increased risk of inguinal hernia with an OR of 1.203 (OR [95%] = 1,04 [1.012 to 1.089], p = 0.008). We identified potential hub genes for inguinal hernia, predicted potential drugs for inguinal hernia, and reverse-validated potential genes by Mendelian randomization. This may provide further insights into asymptomatic pre-diagnostic methods and contribute to studies to understand the molecular mechanisms of risk genes associated with inguinal hernia.

Regionalism as anti-colonialism: imaginaries of area in South East Asian omnibus film and database art

ABSTRACT This article responds to debates about the complicity or outdatedness of regionalism in Area Studies by analyzing creative works by local artists that reimagine South East Asia as ‘area’: Ho Tzu Nyen’s interactive database The Critical Dictionary of Southeast Asia (CDOSEA) (2012–present); and two omnibus films – the Asian Film Archive’s Fragment (2015) and the former Luang Prabang Film Festival’s Mekong 2030 (2020), which feature acclaimed South East Asian filmmakers such as Lav Diaz, U-Wei Haji Saari, Anocha Suwichakornpong, Nawapol Thamrongrattanarit and Tan Chui Mui. Diverging from Caroline Ha Thuc’s earlier South East Asia Research article by revisiting vernacular concepts of sovereignty and collectivity such as mandala and zomia in subaltern historical and anthropological writings, it examines how these works highlight the commonality of motifs of ecology, performance, mobility and spirituality. While the digital artwork CDOSEA algorithmically rearranges constellations of images, words and sounds commonly associated with the region, the omnibus films Mekong 2030 and Fragment combine diverse, fragmentary narratives from different locations within a single anthology. Transforming ‘area’ from an object of neocolonial knowledge production to a source of autonomous collective agency, the article explores how these works visualize a provisional community defined by its plurality, fluidity and inclusiveness.

Drug-drug interactions with oral anticoagulants: information consistency assessment of three commonly used online drug interactions databases in Switzerland.

Background: Toxicity or treatment failure related to drug-drug interactions (DDIs) are known to significantly affect morbidity and hospitalization rates. Despite the availability of numerous databases for DDIs identification and management, their information often differs. Oral anticoagulants are deemed at risk of DDIs and a leading cause of adverse drug events, most of which being preventable. Although many databases include DDIs involving anticoagulants, none are specialized in them. Aim and method: This study aims to compare the DDIs information content of four direct oral anticoagulants and two vitamin K antagonists in three major DDI databases used in Switzerland: Lexi-Interact, Pharmavista, and MediQ. It evaluates the consistency of DDIs information in terms of differences in severity rating systems, mechanism of interaction, extraction and documentation processes and transparency. Results: This study revealed 2'496 DDIs for the six anticoagulants, with discrepant risk classifications. Only 13.2% of DDIs were common to all three databases. Overall concordance in risk classification (high, moderate, and low risk) was slight (Fleiss' kappa = 0.131), while high-risk DDIs demonstrated a fair agreement (Fleiss' kappa = 0.398). The nature and the mechanism of the DDIs were more consistent across databases. Qualitative assessments highlighted differences in the documentation process and transparency, and similarities for availability of risk classification and references. Discussion: This study highlights the discrepancies between three commonly used DDI databases and the inconsistency in how terminology is standardised and incorporated when classifying these DDIs. It also highlights the need for the creation of specialised tools for anticoagulant-related interactions.

EV-COMM: A database of interspecies and intercellular interactions mediated by extracellular vesicles.

Intra- and inter-organismal interactions play a crucial role inthe maintenance and function of individuals, as well as communities. Extracellular vesicles (EVs) have been identified as effective mediators for the communication both within and between species. They can carry and transport molecular cargoes to transmit biological messages. Several databases (ExoBCD, ExoCarta, EVpedia, EV-TRACK, Vesiclepedia) complied the cargoes information including DNA, RNA, protein, lipid and metabolite associated with EVs. Databases that refer to the complete records on both donor and recipient information are warranted to facilitate the understanding of the interaction across cells and species. In this study, we developed a database that compiled the records equipped with a structured process of EV-mediated interaction. The sources of donor and recipient were classified by cell type, tissues/organs and species, thus providing an extended knowledge of cell-cell, species-species interaction. The isolation and identification methods were presented for assessing the quality of EVs. Information on functional cargoes was included, where microRNA was linked to a prediction server to broaden its potential effects. Physiological and pathological context was marked to show the environment where EVs functioned. At present, a total of 1481 data records in our database, including 971 cell-cell interactions belonging to more than 40 different tissues/organs, and 510 cross-species records. The database provides a web interface to browse, search, visualize and download the interaction records. Users can search for interactions by selecting the context of interest or specific cells/species types, as well as functional cargoes. To the best of our knowledge, the database is the first comprehensive database focusing on interactions between donor and recipient cells or species mediated by EVs, serving as a convenient tool to explore and validate interactions. The Database, shorten as EV-COMM (EV mediated communication) is freely available at http://sdc.iue.ac.cn/evs/list/ and will be continuously updated.

Network-based identification of key proteins and repositioning of drugs for non-small cell lung cancer.

NSCLC is a lethal cancer that is highly prevalent and accounts for 85% of cases of lung cancer. Conventional cancer treatments, such as chemotherapy and radiation, frequently exhibit limited efficacy and notable adverse reactions. Therefore, a drug repurposing method is proposed for effective NSCLC treatment. This study aims to evaluate candidate drugs that are effective for NSCLC at the clinical level using a systems biology and network analysis approach. Differentially expressed genes in transcriptomics data were identified using the systems biology and network analysis approaches. A network of gene co-expression was developed with the aim of detecting two modules of gene co-expression. Following that, the Drug-Gene Interaction Database was used to find possible drugs that target important genes within two gene co-expression modules linked to non-small cell lung cancer (NSCLC). The use of Cytoscape facilitated the creation of a drug-gene interaction network. Finally, gene set enrichment analysis was done to validate candidate drugs. Unlike previous research on repositioning drugs for NSCLC, which uses a gene co-expression network, this project is the first to research both gene co-expression and co-occurrence networks. And the co-occurrence network also accounts for differentially expressed genes in cancer cells and their adjacent normal cells. For effective management of non-small cell lung cancer (NSCLC), drugs that show higher gene regulation and gene affinity within the drug-gene interaction network are thought to be important. According to the discourse, NSCLC genes have a lot of control over medicines like vincristine, fluorouracil, methotrexate, clotrimazole, etoposide, tamoxifen, sorafenib, doxorubicin, and pazopanib. Hence, there is a possibility of repurposing these drugs for the treatment of non-small-cell lung cancer.

Program Factors Associated With Improved American Board of Surgery Examination Pass Rates.

The American Board of Surgery awards board certification after successful completion of both the Qualifying Exam and Certifying Exam. Although multiple studies have evaluated board performance at the resident level, fewer studies have evaluated board performance at the program level. Program pass rates, available through the American Board of Surgery, for 2019-2021 were compared to program information through the American Medical Association Fellowship and Residency Electronic Interactive Database Access (FREIDA). A significant positive correlation of Certifying Exam performance to residency length, resident class size, and number of total physician faculty within the program was seen. Greater average hours of didactics per week had a significant positive correlation to improved Qualifying Exam performance but not Certifying Exam. Programs with higher percentages of residents graduating from a United States MD program, compared to international or DO schools, were associated with improved performances. It also appears that more established programs performed better than younger programs <20years old. Programs in the West and Midwest performed significantly better on the Qualifying Exam than programs in the South and Northeast. Board certification serves as the capstone for surgeons after completing general surgery residency. Multiple program factors demonstrate a significant correlation to board performance.

DDID: a comprehensive resource for visualization and analysis of diet-drug interactions.

Diet-drug interactions (DDIs) are pivotal in drug discovery and pharmacovigilance. DDIs can modify the systemic bioavailability/pharmacokinetics of drugs, posing a threat to public health and patient safety. Therefore, it is crucial to establish a platform to reveal the correlation between diets and drugs. Accordingly, we have established a publicly accessible online platform, known as Diet-Drug Interactions Database (DDID, https://bddg.hznu.edu.cn/ddid/), to systematically detail the correlation and corresponding mechanisms of DDIs. The platform comprises 1338 foods/herbs, encompassing flora and fauna, alongside 1516 widely used drugs and 23950 interaction records. All interactions are meticulously scrutinized and segmented into five categories, thereby resulting in evaluations (positive, negative, no effect, harmful and possible). Besides, cross-linkages between foods/herbs, drugs and other databases are furnished. In conclusion, DDID is a useful resource for comprehending the correlation between foods, herbs and drugs and holds a promise to enhance drug utilization and research on drug combinations.

Depletion of CPNE7 sensitizes colorectal cancer to 5-fluorouracil by downregulating ATG9B expression.

We aimed to explore the biological function of CPNE7 and determine the impact of CPNE7 on chemotherapy resistance in colorectal cancer (CRC) patients. According to the Gene Expression Profiling Interactive Analysis database and previously published data, CPNE7 was identified as a potential oncogene in CRC. RT-qPCR and Western blotting were performed to verify the expression of CPNE7. Chi-square test was used to evaluate the associations between CPNE7 and clinical features. Cell proliferation, colony formation, cell migration and invasion, cell cycle and apoptosis were assessed to determine the effects of CPNE7. Transcriptome sequencing was used to identify potential downstream regulatory genes, and gene set enrichment analysis was performed to investigate downstream pathways. The effect of CPNE7 on 5-fluorouracil chemosensitivity was verified by half maximal inhibitory concentration (IC50). Subcutaneous tumorigenesis assay was used to examine the role of CPNE7 in sensitivity of CRC to chemotherapy invivo. Transmission electron microscopy was used to detect autophagosomes. CPNE7 was highly expressed in CRC tissues, and its expression was correlated with T stage and tumour site. Knockdown of CPNE7 inhibited the proliferation and colony formation of CRC cells and promoted apoptosis. Knockdown of CPNE7 suppressed the expression of ATG9B and enhanced the sensitivity of CRC cells to 5-fluorouracil invitro and invivo. Knockdown of CPNE7 reversed the induction of the autophagy pathway by rapamycin and reduced the number of autophagosomes. Depletion of CPNE7 attenuated the malignant proliferation of CRC cells and enhanced the chemosensitivity of CRC cells to 5-fluorouracil.

Identification of potential cell death-related biomarkers for diagnosis and treatment of osteoporosis

BackgroundThis study aimed to identify potential biomarkers for the diagnosis and treatment of osteoporosis (OP).MethodsData sets were downloaded from the Gene Expression Omnibus database, and differentially programmed cell death-related genes were screened. Functional analyses were performed to predict the biological processes associated with these genes. Least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF) machine learning algorithms were used to screen for characteristic genes, and receiver operating characteristics were used to evaluate the diagnosis of disease characteristic gene values. Gene set enrichment analysis (GSEA) and single-sample GSEA were conducted to analyze the correlation between characteristic genes and immune infiltrates. Cytoscape and the Drug Gene Interaction Database (DGIdb) were used to construct the mitochondrial RNA-mRNA-transcription factor network and explore small-molecule drugs. Reverse transcription real-time quantitative PCR (RT-qPCR) analysis was performed to evaluate the expression of biomarker genes in clinical samples.ResultsIn total, 25 differential cell death genes were identified. Among these, two genes were screened using the LASSO, SVM, and RF algorithms as characteristic genes, including BRSK2 and VPS35. In GSE56815, the area under the receiver operating characteristic curve of BRSK2 was 0.761 and that of VPS35 was 0.789. In addition, immune cell infiltration analysis showed that BRSK2 positively correlated with CD56dim natural killer cells and negatively correlated with central memory CD4 + T cells. Based on the data from DGIdb, hesperadin was associated with BRSK2, and melagatran was associated with VPS35. BRSK2 and VPS35 were expectably upregulated in OP group compared with controls (all p < 0.05).ConclusionsBRSK2 and VPS35 may be important diagnostic biomarkers of OP.

RFC3 drives the proliferation, migration, invasion and angiogenesis of colorectal cancer cells by binding KIF14.

Colorectal cancer (CRC) is a deadly and aggressive type of cancer that has a high fatality rate. The expression levels of replication factor C subunit 3 (RFC3) and kinesin family member 14 (KIF14) have been reported to be increased in CRC. The current study aimed to explore the effects of RFC3 on the malignant behaviors of CRC cells and its possible underlying mechanism involving KIF14. RFC3 and KIF14 expression levels in CRC tissues were analyzed using TNMplot database and Gene Expression Profiling Interactive Analysis database bioinformatics tools. RFC3 and KIF14 levels in CRC cells were examined using reverse transcription-quantitative PCR and western blotting. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were performed to assess cell proliferation. Cell apoptosis was determined using flow cytometric analysis. Wound healing and Transwell assays were adopted for the evaluation of cell migration and invasion. Tube formation assay in human umbilical vein endothelial cells was used to measure angiogenesis. Western blotting analysis was performed to determine the expression of apoptosis-, migration- and angiogenesis-associated proteins. Additionally, bioinformatics tools predicted the co-expression and interaction of RFC3 and KIF14, which was verified by a co-immunoprecipitation assay. RFC3 displayed elevated expression in CRC tissues and cells, and depletion of RFC3 halted the proliferation, migration, invasion and angiogenesis, while increasing the apoptosis of CRC cells; this was accompanied by changes in the expression levels of related proteins. In addition, RFC3 bound to KIF14 and interference with RFC3 reduced KIF14 expression. Moreover, KIF14 upregulation reversed the effects of RFC3 depletion on the aggressive cellular behaviors in CRC. In conclusion, RFC3 might interact with KIF14 to function as a contributor to the malignant development of CRC.

G2 and S phase-expressed protein 1 is a biomarker for poor prognosis in lung adenocarcinoma.

Studying the regulatory mechanism and clinical application of G2 and S phase-expressed protein 1 (GTSE1) genes in lung adenocarcinoma (LUAD). LUAD data was obtained from The Cancer Genome Atlas (TCGA) database, and differentially expressed genes (DEGs) were derived by analyzing expression data using R software. Survival analysis was performed to identify genes associated with LUAD, and among them, a target gene for LUAD was identified. Further analysis of the gene expression profiling interactive analysis database revealed differences in gene expression between normal and tumor tissues of LUAD patients. Disease free survival (DFS) and overall survival (OS) of the GTSE1 genes in LUAD were compared. The study conducted a GSEA analysis of GTSE1 expression and further investigated the relationships between GTSE1 expression and the survival time of LUAD patients at different pathological stages. The correlations between OS and GTSE1 gene expression were explored based on different treatments. Additionally, the correlation between the GTSE1 gene and immune infiltration was analyzed. The results indicated that the expression of GTSE1 was significantly higher in tumor tissues of LUAD compared to normal tissues. Furthermore, patients with high GTSE1 expression had significantly lower survival rates for OS and DFS compared to patients with low expression of GTSE1. The GSEA analysis of GTSE1 revealed its involvement in LUAD through the Reactome unwinding of DNA and Biocarta ranms pathway. In patients with LUAD at the pathological T2 stage, low expression of GTSE1 was associated with longer survival time. Furthermore, LUAD patients with low GTSE1 expression who underwent surgery without chemotherapy exhibited a longer survival time. The GTST1 gene, identified as a target gene of LUAD, was validated through cell experiments and pathological sections. GTSE1 can be used as a marker and therapeutic target for LUAD. The survival of LUAD patients can be improved by reducing the expression of GTSE1.

Screening and verification of hub genes in esophageal squamous cell carcinoma by integrated analysis

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. However, the mechanisms underlying ESCC tumorigenesis have not been fully elucidated. Thus, we aimed to determine the key genes involved in ESCC tumorigenesis. The following bioinformatics analyses were performed: identification of differentially expressed genes (DEGs); gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis; integrated analysis of the protein–protein interaction network and Gene Expression Profiling Interactive Analysis database for validation of hub genes. Finally, western blotting and qPCR were used to explore the expression of cell division cycle 6 (CDC6) in ESCC cell lines. Immunohistochemistry analysis of ESCC samples from patients and matched clinical characteristics was used to determine the effects of CDC6. A total of 494 DEGs were identified, and functional enrichment was mainly focused on cell cycle and DNA replication. Biological pathway analysis of the hub genes was closely related to the cell cycle. We found that CDC6 was upregulated in ESCC cell lines and patient tissues and was related to the clinicopathological characteristics of ESCC. In conclusion, this study identified hub genes and crucial biological pathways related to ESCC tumorigenesis and integrated analyses indicated that CDC6 may be a novel diagnostic and therapeutic target for ESCC.

Abstract 3482: Single-cell transcriptome analysis reveals that PLK4 signature genes are highly associated with cancer proliferation and hotspot mutations in non-small cell lung cancer (NSCLC)

Abstract Background: Polo-like kinase 4 (PLK4) is a member of the polo-like kinase family known for its precise regulation during the cell cycle and its key role in centriole duplication, which is essential for proper cell division. Dysregulation of PLK4 is associated with abnormal centriole number, genomic instability and cancer development. In our previous study, we proposed PLK4 as a potential therapeutic target and biomarker for LUAD patients with TP53 mutations by bulk RNA-seq analysis and confirmed its association with drug resistance. In this study, we analyzed the expression of PLK4 and its association with cell cycle at the cellular level by scRNA-seq in NSCLC data. Methods: In a previous study, we analyzed NSCLC data from The Cancer Genome Atlas (TCGA) database using the UCSC Xena data portal. In this study, we analyzed E-MTAB-6653 dataset from the single cell expression atlas(https://www.ebi.ac.uk/gxa/sc/home). Results: In the previous study, we demonstrated that PLK4 expression is higher in primary tumors compared to normal tissues in NSCLC. Higher PLK4 expression in patients is associated with an unfavorable prognosis. Using genes highly correlated with PLK4, we confirmed a significant association between PLK4 and TP53 mutation by statistical analysis. Using the Drug Gene Interaction database, we observed an association between the drug resistance-related genes PBK and BIRC5 with PLK4, and these genes were also correlated with TP53 mutation. In this study, we investigated the association between PLK4 and the cell cycle using single cell RNA-seq. First, we performed data pre-processing to selectively isolate NSCLC cells. Using a set of 87 PLK4 signature genes obtained from previous research, we stratified the samples into PLK4 high and low groups based on the expression of these genes. We then analyzed cell cycle related genes in both groups and observed a higher expression of G2/M phase related genes in the PLK4 high group compared to the PLK4 low group. We also examined the expression of PLK4 signature genes based on pathological differences and found higher expression in tumor tissue compared to normal tissue. There was also an increasing expression gradient from the tumor margin to the tumor core. Finally, using Gene Ontology analysis of both groups, we confirmed the upregulation of genes associated with transcription and translation, as indicated by the GO terms obtained. Conclusion: In a previous study, the association between PLK4 expression, TP53 mutation and drug resistance was identified by bulk RNA-seq. In the current study, we used single cell RNA-seq to verify the correlation between PLK4 and cell cycle in NSCLC. In addition, we observed that the expression of PLK4 signature genes increased towards the tumor core based on pathological differences. Citation Format: Youngtaek Kim, Joon Yeon Hwang, YoungJoon Park, Dong Kwon Kim, Kwangmin Na, Seul Lee, Sujeong Baek, Seong-san Kang, Seung Min Yang, Mi Hyun Kim, Heekyung Han, Chai Young Lee, Yu Jin Han, Min Hee Hong, Jii Bum Lee, Sun Min Lim, Kyoung-Ho Pyo, Byoung Chul Cho. Single-cell transcriptome analysis reveals that PLK4 signature genes are highly associated with cancer proliferation and hotspot mutations in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3482.